The investigators of this proposal have developed two tools that may be of value in establishing stable mixed chimerism of patients with sickle cell anemia and beta thalassemia. The first tool is directed toward developing a minimally toxic method for producing stem cell depletion using the combination of flt-3 ligand (FL) and 5-fluorouracil (5-FU). This approach may be a useful component of transplant conditioning regimens that are directed at achieving mixed chimerism. The second tool uses chemical inducers of dimerization (CIDs) to specifically deliver a mitogenic signal to genetically modified cells. Transfer of a gene that encodes a CID-responsive protein may render normal donor stem cell responsive to CID-mediated proliferation. This approach may allow the proliferative status of normal donor stem cells in mixed chimeras to come under direct pharmacological control. Specific Aim 1 tests whether CIDs can expand genetically modified stem and progenitor cells in vivo. Specific Aim 2 develops a mouse model of mixed chimerism in beta thalassemia, and seeks to determine the level of normal donor stem cell engraftment needed to reverse the thalassemic phenotype. Specific Aim 3 tests whether CID-mediated in vivo expansion of normal donor stem cells can correct the thalassemic phenotype of mice with mixed chimerism. Specific Aim 4 evaluates whether FL can sensitize stem ells to 5-FU. In Specific Aim 5, the FL/5-FU combination is added to an immunosuppressive condition regimen for studies in allogeneic models of mixed chimerism. In Specific Aim 6, findings from the previous specific aims are combined to test CID-mediated in vivo expansion of normal donor stem cells in an allogeneic model of mixed chimerism.